Mol. Hum. Reprod. Advance Access originally published online on July 16, 2004
Molecular Human Reproduction 2004 10(9):671-676; doi:10.1093/molehr/gah090
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Influence of peroxisome proliferator-activated receptor 
activation by its endogenous ligand 15-deoxy 
12,14 prostaglandin J2 on nitric oxide production in term placental tissues from diabetic women
1Laboratory of Reproduction and Metabolism, CEFYBO-CONICET, Serrano 669, C1414DEM Buenos Aires and 2Obstetrics and 3Nutrition Departments, Carlos G.Durand Hospital, Buenos Aires C1414DEM, Argentina
4 To whom correspondence should be addressed. Email: elidate{at}fibertel.com.ar
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Abstract |
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Diabetes induces alterations which condition placental remodelling. The levels of nitric oxide (NO) (a modulator of placental invasiveness, differentiation and proliferation) were higher in term placental explants from diabetic patients when compared to controls. Peroxisome proliferator-activated receptor
(PPAR) activation by its endogenous ligand 15-deoxy 
12,14prostaglandin J2 (15dPGJ2), is a differentiating factor of adipocytes and other cell types, such as trophoblasts. 15dPGJ2 is also able to down-regulate NO production in different cell types. Our study evaluated the levels of 15dPGJ2 and PPAR and the influence of PPAR activation by 15dPGJ2 on the production of NO, in term placental tissues from control, pre-gestational and gestational diabetic patients. Our results showed that 15dPGJ2 was present in human term placenta, and that its levels were diminished in gestational (P<0.05) and pre-gestational (P<0.002) diabetic women when compared to controls. Exogenous 15dPGJ2 addition (2 x 10–6 mol/l) down-regulated NO production in placenta from control (P<0.001) and pre-gestational diabetic (P<0.01) patients, but failed to do so in gestational diabetic women, whose placental PPAR expression was diminished in comparison to controls (P<0.001). As the exogenous activation of PPAR prevented NO overproduction in placenta from pre-gestational diabetic women, it may have the potential to improve fetal outcome in this pathology.
Key words:
diabetes/nitric oxide/placenta/PPAR/15dPGJ2
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Introduction |
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The placenta is critical during all pregnancy stages. The trophoblasts attach to and invade into the maternal endometrium during implantation, and over the following weeks, the placenta proliferates and produces hormones which influence the maternal metabolic behavior, thus ensuring the supply of nutrients to the fetus. When exposed to an adverse maternal metabolic imbalance, several alterations take place in the placenta in order to compensate for this environmental failure. In diabetes mellitus, the alterations in the levels and function of vasoactive and pro-inflammatory agents (Coughlan et al., 2001
; Saldeen et al., 2002), and in the regulation of placental intermediary metabolism (Herrera et al., 1986), condition placental development and remodelling, and adversely affect the outcome of pregnancy. Maternal hyperglycaemia leads to an increase in DNA (Winick and Noble, 1967), glycogen and lipid (Diamant et al., 1982) contents in the placenta and to placentomegaly (Clarson et al., 1989). Immature villi, enlargement of the surface and thickening of the villous basement membrane and impaired trophoblast proliferation are frequently found in the diabetic placenta (Mayhew et al., 1994; Younes et al., 1996). Hyperglycaemia is also responsible for the stimulation of the mitochondrial electron transport chain, which induces high levels of free oxygen radicals, and for the non-enzymatic glycation of plasma proteins, which increases the formation of advanced glycation end-products (AGE) (Piconi et al., 2003). Indeed, signs of oxidative stress are found in term placental tissues from diabetic patients (Pustovrh et al., 2000).
Nitric oxide (NO) is a main regulator of placental blood flow (Resnik, 1983), and is also able to modulate trophoblast differentiation and invasiveness, and angiogenesis during placental development (Ahmed and Perkins, 2000; Novaro et al., 2001; Yang et al., 2003).
Levels of NO production are higher in term placental tissues from diabetic patients when compared to controls (Figueroa et al., 2000; Pustovrh et al., 2000). This overproduction is probably originated by an increased expression and activity of either the Ca2+-independent or the endothelial isoform of nitric oxide synthase (iNOS and eNOS respectively) (Schonfelder et al., 1996; Rossmanith et al., 1999). When both NO and reactive oxygen species (ROS) are increased, the peroxynitrite anion is generated. This potent oxidant alters the structure and functions of lipids and proteins, altering enzyme activity and disrupting cell signalling pathways (Szabo, 2003). High levels of nitrotyrosine residues, an index of the presence of peroxynitrites, are found in the villous stroma and fetoplacental vessels from diabetic women at term (Lyall et al., 1998; Kossenjans et al., 2000).
15-Deoxy 12,14prostaglandin J2 (15dPGJ2) is a cyclopentenone-type prostaglandin that lacks cell surface receptors, but is actively transported into cells where it exerts a variety of biological effects, including the modulation of cell growth and the regulation of the activity and expression of different enzymes. 15dPGJ2 is the naturally occurring main ligand for the peroxisome proliferator-activated receptor (PPAR).
The 15dPGJ2-activated PPAR is a key regulator of both adipogenesis and lipid uptake and efflux (Kliewer et al., 1994), and is a central differentiation factor of various cell types including placental trophoblasts (Barak et al., 1999). In addition, PPAR activation potently suppresses inflammatory processes through the down-regulation of genes encoding for pro-inflammatory enzymes such as cyclooxygenase-2 and iNOS (Ricote et al., 1998; Shibata et al., 2002). However, there is little information about the regulation of inflammatory processes by PPAR in placental tissues. Both NO and 15dPGJ2 are putative regulators of the remodelling changes subserved by the placenta throughout pregnancy (implantation, proliferation and growth), and alterations in their levels may be critical for the fetal development in maternal diabetes.
The aim of the present study was to determine the levels of 15dPGJ2 and PPAR, and the influence of PPAR activation by its endogenous ligand on the production of NO in term placental tissues from control, pre-gestational and gestational diabetic patients.
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Materials and methods |
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15dPGJ2 and the enzyme immunoassay kit for determination of 15dPGJ2 were purchased from Assay Designs Inc. (USA). Nitrate/nitrite assay kit was purchased from Cayman Chemical Co. (USA). Bisphenol A diglycidyl ether (BADGE), nitrocellulose membranes (0.45 mm pore size), bovine serum albumin, 5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium tablets, sodium dodecyl sulphate (SDS), Triton X-100, protease inhibitor cocktail, molecular weight standards 6.5–200 kDa and image analysis program Sigmagel were obtained from Sigma Chemical Co. (USA). Polyclonal rabbit PPAR
antiserum was obtained from Santa Cruz Biotechnology (USA). Acrylamide, N'N'-bis methylene-acrylamide, ammonium persulphate, tri-hydroxymethyl aminomethane, glycine and TEMED were purchased from BioRad Laboratories (USA). Glucose, fructosamine and triglyceride quantification systems were obtained from Roche Diagnostics (Argentina).
Tissue preparation
Term placental tissues were obtained from uncomplicated pregnancies (controls) (n=12) and from women with either pre-gestational insulin-dependent diabetes mellitus (PGD) (n=9) or gestational diabetes mellitus (GD) (n=11), immediately after vaginal delivery (50%) or Caesarean section (50%) at term in the Department of Obstetrics and Gynecology at Carlos G.Durand Hospital, Buenos Aires, Argentina, with approval of the Institutional Review Board. After a brief rinse in cold Krebs Ringer bicarbonate buffer (KRB), ionic composition (mmol/l): Na+ 145, K+ 5.9, Ca2+ 2.2, Mg2+ 1.2, Cl– 127, HCO3– 25, SO42– 1.2, PO43– 1.2, the samples were placed in a sealed glass bottle with KRB, and immediately carried on ice to the experimental laboratory. In the laboratory, villous samples were taken midway between the chorionic and basal plates. A group of samples was stored a –70°C for the determination of 15dPGJ2 and PPAR levels, and another group was incubated in the presence or absence of either 15dPGJ2 or BADGE, and subsequently evaluated for nitrates/nitrites production.
15dPGJ2 determinations
15dPGJ2 was measured in placental tissues from control, PGD and GD patients employing an enzyme-linked immunosorbent asay (ELISA) commercial kit. Placental tissues were homogenized in 100 mmol/l Tris–hydroxymethyl aminomethane (Tris–HCl) buffer. An aliquot was separated for protein determination by Bradford (1976), and then centrifuged. Placental prostaglandins in the precipitate were extracted twice in absolute ethanol and the extracts were dried in a Savant (USA) Speed-Vac concentrator and stored at –70°C until ELISA. When the assay was performed, the extracts were reconstituted with 50 ml ethanol and 200 ml of Assay Buffer provided by the commercial kit. Briefly, the kit uses a polyclonal antibody against 15dPGJ2 to bind competitively the prostaglandin in the sample or an alkaline phosphatase molecule which has 15dPGJ2 covalently attached to it. Cross-reactivities of the employed antibody are 49% for PGJ2, 6% for 12,14PGJ2, 5% for PGD2 and <0.01% for arachidonic acid and other prostanoids such as PGE2, PGF2
and thromboxane B2. After a simultaneous incubation, a p-nitrophenyl phosphate substrate is added, and the generated yellow colour is evaluated on a microplate reader at 405 nm. The results were expressed as pg per mg protein.
Nitrates/nitrites assay
The placental nitrate and nitrite concentrations were quantified employing an assay kit for nitrate and nitrite determinations, as follows: placental explants were incubated in a metabolic shaker, under an atmosphere of 5% CO2 in 95% O2 at 37°C for 1 h in KRB medium. The incubating medium was added with either 15dPGJ2 (2 x 10–6 mol/l) or BADGE (10–6 mol/l), and the incubating medium without any additions was used for control. The tissues were then stored at –70°C until the evaluation. When the assay was performed, the placental strips were homogenized in 100 mmol/l Tris–HCl buffer, an aliquot was separated for protein determinations and then centrifuged. Nitrates in the supernatant were reduced to nitrites using nitrate reductase, and total nitrites were measured by the Griess method (Green et al., 1982). Optimal densities were measured at 540 nm in a microtitre plate using NaNO3 and NaNO2 as standards. Results were expressed as nmol per mg protein.
Western blot for PPAR
Placental tissue (100 mg) was homogenized in 200 ml of ice-cold lysis buffer (20 mmol/l HCl pH 7.4, 150 mmol/l NaCl, 1% Triton X-100 and 5 ml protease inhibitor cocktail) and incubated on ice for 2 h. Tissue homogenates were centrifuged at 10 000 rpm for 10 min and the supernatant removed. Protein concentrations were determined. Equal amounts of protein samples (250 µg per lane) were separated with the use of 8% SDS–polyacrylamide gel electrophoresis. Proteins were then transferred to a nitrocellulose membrane, which was blocked with 1% BSA for 1.5 h to inhibit non-specific binding and then incubated with a polyclonal rabbit IgG antibody to PPAR (1:200) at room temperature for 1 h. The antibody employed (sc-7194, Santa Cruz Biotecnology Inc.) is not cross-reactive with PPAR or PPARß and is raised against an epitope corresponding to the N-terminus of PPAR that is conserved in human, rat and mouse. The blots were washed, incubated with goat anti-rabbit antibody conjugated with alkaline phosphatase for 1 h and revealed with 5-bromo-4-chloro-3-indolyl phosphate/Nitroblue Tetrazolium (1:2000) to visualize the PPAR bands. The identity of PPAR was established by the employment of brown adipose tissue from adult rats as a positive control and by the use of molecular weight standards, both of which allow the identification of a major band at the expected size of 50 kDa. The relative intensity of protein signals was quantified by densitometric analysis using the Sigma Gel Program.
Biochemical determinations
Maternal circulating glucose, triglyceride and fructosamine levels from GD and PGD patients were quantified on the third trimester of pregnancy, by Roche Diagnostics System–Hitachi 911 Autoanalyzer. In addition the GD group was submitted to an oral glucose tolerance test (OGTT) with a challenge of dextrose (75 g), and glycaemia was quantified 120 min after the glucose ingestion.
Statistics
Data were expressed as means±SEM. Comparisons between groups were performed employing one-way analysis of variance in conjunction with the Tukey's test. Differences between groups were considered significant when P<0.05.
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Results |
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Patients' data
The clinical characteristics of the pregnant women and the neonates evaluated are shown in Table I. Fetal birth weight and time of gestation were similar in control and diabetic patients.
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Serum fructosamine levels were elevated in PGD patients and slightly above normal levels (normal levels being up to 150 mmol/l) in GD women. Basal circulating triglycerides were normal in PGD patients (normal levels up to 160 mg/dl), and were increased in the GD group. Basal glycaemic levels were higher in GD women than in controls (P<0.01). One hundred and twenty minutes after the oral glucose challenge (normal value up to 7 mmol/l) (Asociación Latinoamericana de Diabetes(ALAD), 1997
), the levels of glucose from GD patients were abnormally increased. PGD patients exhibited basal glycaemia values higher than those obtained from the control and the GD groups (P<0.001).
Placental levels of 15dPGJ2
Placental production of 15dPGJ2, the strongest endogenous ligand for PPAR, was evaluated in explants from control, GD and type 1 PGD women at term (Figure 1). 15dPGJ2 levels were diminished in the GD group (P<0.05) when related to controls, and were even lower in the type 1 PGD patients (P<0.002).
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Influence of 15dPGJ2 on nitrates/nitrites placental production
Placental explants from control, GD and type 1 PGD women at term were incubated either with or without 15dPGJ2 (2 x 10–6 mol/l) in order to evaluate the influence of the cyclopentenone on the placental levels of nitrates and nitrites, stable metabolites employed as an index of NO production. BADGE (10–6 mol/l), an antagonist of PPAR
, was added to another group of samples, in order to evaluate whether the activation of the nuclear receptor is implicated in the regulatory action of 15dPGJ2 on NO placental levels. Figure 2 shows that nitrate/nitrite levels were higher in placental tissue from GD (Figure 2B) and PGD (Figure 2C) (P<0.001) patients than in controls (Figure 2A), and diminished in the presence of 15dPGJ2 in the placenta from both control (Figure 2A) and PGD (Figure 2C) patients (P<0.001 and P<0.01 respectively). On the other hand, the presence of BADGE induced an increase of nitrate/nitrite levels when compared to basal concentrations in both control (P<0.02, Figure 2A) and PGD (P<0.01, Figure 2C) groups. These results suggest that both exogenous and endogenous 15dPGJ2 regulates placental NO production, and indicate the involvement of PPAR activation in the modulation of the placental nitridergic pathway. Neither the cyclopentenone nor the antagonist of PPAR were able to modify nitrate/nitrite levels in placental explants from GD patients (Figure 2B).
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Term placental PPAR
levelsAs PPAR
activation regarding NO production was significantly altered in placental tissues from GD women, we were prompted to evaluate PPAR expression in placental explants from control, GD and type 1 PGD women at term. Figure 3 shows that PPAR was expressed in term placental tissues from the three evaluated groups. In placenta from GD women, the levels of immune-detectable PPAR were lower than in controls (P<0.01), while in placenta from PGD women, these levels were similar to controls.
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Discussion |
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Sub-optimal maternal metabolism, such as that found in diabetic pregnancies, may adversely affect placental physiology and may be reflected in embryo dysmorphogenesis, abnormal fetal growth and higher risks of cardiovascular disease and diabetes in later life of the offspring (Barker, 1999
; Aerts and Van Assche, 2003). Our work is focused on the involvement of vasoactive agents such as NO, ROS and PPAR ligands in healthy placental remodelling processes, and also in the alteration of the levels of these agents and their modulatory mechanisms in diabetic pregnancies. Our group has previously reported that embryos from diabetic rats produce diminished amounts of 15dPGJ2 during organogenesis when compared to controls (Jawerbaum et al., 2002), and that the cyclopentenone levels are also decreased in isolated pancreatic islets from diabetic animals (González et al., 2001). In the present work we found that 15dPGJ2 was produced by human placenta, and that its levels were lower in term placental explants from both PGD and GD women than in control tissues. Although the uptake and production of arachidonic acid (AA) and its metabolization to eicosanoids are much increased in the human term placenta in type I diabetes (Kuhn et al., 1990a), the relative amounts of AA metabolites are altered, leading to an increased ratio of thromboxane A2 to prostaglandin I2 (Kuhn et al., 1990b; White et al., 2002), which contributes to the dysfunction of diabetic placenta. Our findings show that the cyclopentenone placental production is inversely related to the severity of maternal diabetes, suggesting that hyperglycaemia may affect the 15dPGJ2 synthetic pathway.
15dPGJ2 is a potent anti-inflammatory agent that represses the expression of a number of genes including those encoding for iNOS, the transcription factor NF-
B and its activating kinase (Rossi et al., 2000). The present results show that 15dPGJ2 was able to down-regulate the production of human placental NO and to diminish even the high NO levels found in type 1 diabetic tissues. The low levels of 15dPGJ2 found in this work may be related to the increased NO production found in the placenta from diabetic patients. This placental elevated NO may lead to increased amounts of peroxynitrites, inducing damage in this tissue.
Previous reports have shown high levels of eNOS mRNA in syncytiotrophoblasts from term placenta from diabetic patients (Rossmanith et al., 1999), and an elevated expression of iNOS in placenta from GD women (Schonfelder et al., 1996). However, it seems that there may be regional differences in the expression of NOS isoforms in the placenta affected by diabetes (Desoye et al., 2003), since other authors found no differences in the activity of total NOS or iNOS in homogenized placental tissues from diabetic women when compared to controls (Di Iulio et al., 1999). Our experimental procedure did not allow us to distinguish between the different placental regions or structures exposed to the fetal or to the maternal circulation. On the other hand, we cannot exclude the possibility of the generation of nitrites originated from the enzyme myeloperoxidase, that is located on the term placental endothelium (Hammer et al., 2001).
The findings of the present work are in line with our previous observations in experimental models of diabetes in the rat, where exogenous 15dPGJ2 added to the incubating medium prevents the diabetes-induced increase of embryonic NO levels during organogenesis (Jawerbaum et al., 2002), and where it is also able to decrease both the production of nitrates/nitrites and the activity of NOS in isolated pancreatic islets, thus limiting the inflammatory damage of ß cells (González et al., 2001).
Some accumulated evidence suggests that 15dPGJ2 effects may be exerted through PPAR-dependent and -independent molecular mechanisms (Kliewer et al., 1994; Strauss et al., 2000; González et al., 2001). In this work the blockade of PPAR by the antagonist BADGE resulted in an increase of endogenous NO production from control and PGD placenta. These findings suggest that the cyclopentenone is probably modulating placental nitridergic levels at least in part through the activation of the nuclear receptor PPAR.
In spite of similair levels of expression of PPAR receptors, the levels of 15dPGJ2 are greatly reduced in the PGD group, compared to control tissue, an alteration probably involved in the increased NO placental production in these patients. On the other hand, the GD group showed lower levels of endogenous 15dPGJ2 than those of controls, and the expression of PPAR was also diminished, an alteration that may be related to the lack of regulation of NO levels by the addition of exogenous 15dPGJ2 or by the presence of BADGE.
The present results suggest that NO levels in the placenta from control and type 1 PGD patients are regulated by PPAR, and that there is a failure of this regulatory mechanism in placenta from GD patients. Additional evidence is needed to explore the relationship between these alterations and the abnormal lipid metabolism in these patients.
As a result of long periods of exposure to maternal hyperglycaemia, ROS are enhanced in both fetal and placental tissues from diabetic experimental models and patients (Kossenjans et al., 2000; Kinalski et al., 2001). These high levels of ROS can interact with the high levels of NO, leading to the production of peroxynitrites, which are potent cellular toxic molecules that cause peroxidation and nitrosylation of tyrosine residues and affect signal pathways, and thus may compromise placental structure and functions. Our findings have clinical relevance since the therapeutic interventions that lead to the exogenous activation of PPAR may prevent the overproduction of NO in diabetic placenta, ameliorating the placental alterations that influence the fetal outcome in diabetic pregnancies.
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Acknowledgements |
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We gratefully acknowledge the technical assistance of Mrs María Esther Castro. This research was sponsored by Grant PIP 2529/99 (Alicia Jawerbaum), by Grant PIP 05/98 (Elida González), both of them from the Consejo Nacional de Investigaciones Científicas y Técnicas of Argentine and by Grant PICT 05-10652 (Elida González) from the Agencia Nacional de Promoción Científica y Tecnológica (ANPCYT).
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Submitted on February 10, 2004; resubmitted on June 19, 2004; accepted on June 25, 2004.
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R. Higa, E. Gonzalez, M.C. Pustovrh, V. White, E. Capobianco, N. Martinez, and A. Jawerbaum PPAR{delta} and its activator PGI2 are reduced in diabetic embryopathy: involvement of PPAR{delta} activation in lipid metabolic and signalling pathways in rat embryo early organogenesis Mol. Hum. Reprod., February 1, 2007; 13(2): 103 - 110. [Abstract] [Full Text] [PDF]
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A Jawerbaum, R Higa, V White, E Capobianco, C Pustovrh, D Sinner, N Martinez, and E Gonzalez Peroxynitrites and impaired modulation of nitric oxide concentrations in embryos from diabetic rats during early organogenesis Reproduction, November 1, 2005; 130(5): 695 - 703. [Abstract] [Full Text] [PDF]
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